I am requesting a Recovery Act Competitive Revision (Notice Number: NOT-OD-09-058, NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications) to my NINDS grant R01 NS047452- 05 titled "Characterization of Striatal Nitric Oxide Signaling" (PI: Anthony R. West). Current drug therapies may ameliorate motor symptoms associated with Parkinson's disease (PD), but lose effectiveness with time and produce debilitating side effects such as dyskinesias. Recent studies suggest that alterations in striatal cyclic nucleotide homeostasis are critically involved in the expression of PD motor complications and may underlie adaptive changes in basal ganglia circuits observed following prolonged treatment with levodopa (L-DOPA). Striatal medium-sized spiny neurons (MSNs) contain high levels of soluble guanylyl cyclase (sGC) and cGMP effector targets. A major finding from studies funded by the parent grant is that striatal nitric oxide signaling increases the responsiveness of MSNs to excitatory synaptic transmission largely via activation of sGC-cGMP signaling. Striatal sGC activity/expression is reported to be abnormally elevated in parkinsonian rodents, which may contribute to pathologically high cGMP levels and increased corticostriatal transmission. We have shown that disruption of sGC activity in 6-hydroxydopamine (6-OHDA) lesioned rats reverses pathological elevations in the spontaneous firing of striatal neurons. Furthermore, we have found that of sGC inhibition transiently attenuated the reduction in adjusting steps observed in the contralateral forelimb of 6-OHDA-lesioned rats. Given the above, we hypothesize that persistent elevations in sGC-cGMP signaling contribute to the enduring increases in spontaneous and cortically-evoked spike activity observed in the DA-depleted striatum. Moreover, we anticipate that chronic administration of a sGC inhibitor will partially reverse akinesia and limb use asymmetry observed in DA-depleted rats. Adjunctive therapy combining a sGC inhibitor with L-DOPA is expected to reduce the effective dose of L-DOPA required to treat motor symptoms and decrease the incidence and severity of dyskinesias associated with L-DOPA treatment in 6-OHDA-lesioned rats. We will examine our hypotheses in two aims. Aim 1 will determine the impact of chronic DA depletions on striatal cGMP synthesis and neuronal activity using concurrent measures of extracellular cGMP levels and neuronal activity. Aim 2 will assess the utility of sGC inhibition as mono- and adjunctive therapy for treating motor dysfunction in DA-depleted rats. We anticipate that the proposed investigations will provide a foundation for understanding the impact of dysregulation of sGC-cGMP signaling on electrophysiological changes in glutamatergic transmission occurring in vivo in the parkinsonian striatum. Furthermore, these studies may reveal novel drug targets within cyclic nucleotide signaling cascades for treating movement disorders including akinesia and L-DOPA-induced dyskinesias which are associated with abnormal corticostriatal transmission. PUBLIC HEALTH RELEVANCE: Motor disorders such as Parkinson's disease, Tourette syndrome, Huntington's disease and others afflict an estimated 50 million Americans annually. Further studies examining the nature of the neural systems involved in the modulation of movement are essential for understanding, diagnosing, and treating these debilitating disorders. We anticipate that our proposed studies examining the physiological basis of neurotransmitter interactions in the basal ganglia will produce valuable insights into the mechanisms involved in the generation of purposeful movement and identify more efficacious treatment strategies for patients suffering from movement disorders.